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Lymphoma

Analysis of the host pharmacogenetic background for prediction of outcome and toxicity in diffuse large B-cell lymphoma treated with R-CHOP21

Leukemia volume 23, pages 1118–1126 (2009)Cite this article

Abstract

Knowledge on the impact of pharmacogenetics in predicting outcome and toxicity in diffuse large B-cell lymphoma (DLBCL) is scant. We tested 106 consecutive DLBCL treated with R-CHOP21 for 19 single nucleotide polymorphisms (SNPs) from 15 genes potentially relevant to rituximab-CHOP (R-CHOP) pharmacogenetics. Associations of SNPs with event-free survival (EFS) and toxicity were controlled for multiple testing. Genotypic variants of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase p22phox (CYBA rs4673) and alpha1 class glutathione S-transferase (GSTA1 rs3957357) were independent predictors of EFS (CYBA rs4673 TT genotype: HR 2.06, P=0.038; GSTA1 rs3957357 CT/TT genotypes: HR 0.38, P=0.003), after adjusting for International Prognostic Index (IPI). CYBA rs4673 and GSTA1 rs3957357 also predicted outcome in DLBCL subgroups by IPI. Impact of SNPs on toxicity was evaluated in 658 R-CHOP21 courses utilizing generalized estimating equations. NCF4 rs1883112 was an independent predictor against hematologic (odds ratios (OR): 0.45; P=0.018), infectious (OR: 0.46; P=0.003) and cardiac toxicity (OR: 0.37; P=0.023). Overall, host SNPs affecting doxorubicin pharmacodynamics (CYBA rs4673) and alkylator detoxification (GSTA1 rs3957357) may predict outcome in R-CHOP21-treated DLBCL. Also, NCF4 rs1883112, a SNP of NAD(P)H oxidase p40phox, may have a function in protecting against hematologic and nonhematologic toxicity. These results highlight the need to improve characterization of the host genetic background for a better prognostication of DLBCL.

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Acknowledgements

This study was supported by Ricerca Sanitaria Finalizzata and Ricerca Scientifica Applicata, Regione Piemonte, Torino, Italy; Progetto Integrato Oncologia, Ministero della Salute, Rome, Italy; PRIN 2006, Rome, Italy; Progetto Alfieri, Fondazione CRT, Torino, Italy and Novara-AIL Onlus, Novara, Italy.

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Author notes

  1. D Rossi and S Rasi: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology, Department of Clinical and Experimental Medicine and BRMA, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy

    D Rossi, S Rasi, S Franceschetti, D Capello, A Castelli, L De Paoli, A Conconi & G Gaidano

  2. Division of Pathology, Department of Clinical and Experimental Medicine and BRMA, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy

    A Ramponi

  3. Division of Hematology, Department of Oncology, Azienda Ospedaliera S. Giovanni Battista, Turin, Italy

    A Chiappella & U Vitolo

  4. Division of Hematology, Department of Clinical and Preventive Medicine, University of Milano Bicocca, Monza, Italy

    E M Pogliani

  5. Laboratory of Experimental Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

    I Kwee & F Bertoni

  6. Dalle Molle Institute for Artificial Intelligence, Manno, Switzerland

    I Kwee

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  1. D Rossi
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Correspondence to D Rossi.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Rossi, D., Rasi, S., Franceschetti, S. et al. Analysis of the host pharmacogenetic background for prediction of outcome and toxicity in diffuse large B-cell lymphoma treated with R-CHOP21. Leukemia 23, 1118–1126 (2009). https://doi.org/10.1038/leu.2008.398

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